Neurotropic viruses are important causes of morbidity and mortality throughout the world. The lack of therapeutic options for these diseases is driven by the paucity of understanding of the mechanisms by which neurotropic viruses cause disease. We propose to study the mechanisms responsible for viral-induced neuronal death. Based on our preliminary data, we will evaluate the roles of c-Jun N-terminal kinase (JNK) and transforming growth factor (TGF) -beta signaling during viral infection of primary cortical neurons and in the CMS of a mouse encephalitis model. Once these pathways are characterized in the reovirus model of encephalitis, we also propose to examine these events in human brain tissue obtained from patients infected with West Nile virus and herpes simplex virus. The specific role of these signaling pathways in viral-induced neuronal death is not known. In this application, we plan to characterize the role of JNK and TGF-beta signaling in virus-induced neuronal apoptosis and CNS injury in mice using multiple methods of protein analysis, viral manipulation, viral mutants, gene array analysis, real time-PCR, and laser-capture microdissection techniques. Human samples of brain tissue will then be evaluated using the techniques used for study in the reovirus model of infection. The study of mechanisms responsible for viral-induced cell death is critical to the development of new targeted therapies and neuroprotective strategies for viral infections of the brain and spinal cord. No effective therapy currently exists for West Nile virus infection and the discovery for new therapies or neuroprotective strategies is needed desperately. While acyclovir therapy is effective for herpes simplex encephalitis, morbidity and mortality are still prominent in infected patient and additional strategies to treat this disease would improve outcomes in these patients. I have devoted my professional education to the development of research skills. The Mentored Clinical Scientist Development award will be instrumental in the completion of my training in a supportive mentored environment with a multitude of educational resources available to complete my immediate goal of training to be a clinical scientist and completing my long-term goal of becoming an independent clinician scientist.